Endothelial NO synthase (eNOS, NOS-III) belongs to a group of three isoenzymes which produce nitric oxide (nitrogen monoxide, NO) by oxidation of arginine. Endothelially released NO is of central importance in a number of key cardiovascular mechanisms. It has a vasodilating effect and inhibits the aggregation of platelets, the adhesion of leukocytes to the endothelium and the proliferation of intimal smooth muscle cells.
Endothelial NO synthase is subject to physiological and pathophysiological regulation both at the transcriptional and at the post-transcriptional level. Enzyme already present in the endothelium may undergo calcium-dependent and calcium-independent activation through phosphorylation of specific amino acids, but also by direct interactions with specific proteins. Stimulators of this, usually transient, NO release are extracellular arginine, 17β-estrogen and the mechanical stimulus exerted on the luminal surface of the endothelium by the blood flow (shear stress). The latter additionally leads to regulation of eNOS at the transcriptional level. Thus, for example, Sessa et al. (Circ. Research 74 (1994) 349) were able to obtain a marked increase in eNOS by means of exercise training and the increase in shear stress associated therewith.
Whether regulation at the post-transcriptional level is relevant in vivo, has not been unambiguously proven. Thus, for example, administration of a high arginine dose is followed by only a transient improvement in the endothelium-dependent vasorelaxation in patients with coronary heart disease.
On the other hand, the significance of the upregulation of the eNOS protein is scientifically accepted. Thus, there are findings which show that the protective properties of the HMG-CoA reductase inhibitor simvastatin can be attributed, besides to the lipid lowering, also in part to an increase in eNOS expression in vivo (Endres et al., Proc. Natl. Acad. Sci. USA 95 (1998) 8880). It is additionally known that single point mutations in the 5′-flanking region of the eNOS gene (“eNOS promoter”), and the reduction in the rate of eNOS gene transcription associated therewith, in the Japanese population is associated with an increase in the risk of coronary spasms (Nakayama et al., Circulation 99 (1999) 2864).
The current assumption therefore is that the transcriptional and post-transcriptional mechanisms of eNOS regulation are seriously disturbed in a large number of disorders, especially in cardiovascular disorders. Even in very early stages of a wide variety of cardiovascular disorders it is possible for a dysfunction of this type in the endothelium lining the blood vessels to lead to a deficiency of bioactive NO, which is manifested as the disorder progresses in the form of measurable pathophysiological and morphological changes. Thus, critical steps in early atherogenesis are speeded up by a decrease in endothelial NO release, such as, for example, the oxidation of low density lipoproteins, the recruitment and deposition of monocytes in the intima of vessels, and the proliferation of intimal cells. A consequence of atherogenesis is the formation of plaques on the inside of the blood vessels, which may in turn lead, through a diminution in the shear stress, to a further decrease in endothelial NO release and a further deterioration in the pathology. Since endothelial NO is also a vasodilator, a decrease thereof frequently also leads to hypertension which may, as an independent risk factor, cause further organ damage.
The aim of a therapeutic approach to the treatment of these disorders must accordingly be to interrupt this chain of events by increasing the endothelial NO expression. Gene transfer experiments which lead in vitro to overexpression of NO synthase in previously damaged vessels are in fact able to counteract the described processes and are thus evidence of the correctness of this approach (Varenne et al., Hum. Gene Ther. 11 (2000) 1329).
Some low molecular weight compounds which, in cell cultures, may lead to a direct effect on eNOS transcription and expression are disclosed in the literature. For the statins, as has already been mentioned, it has been possible to show such an increase in eNOS in vivo as a side effect. In view of the known range of side effects of this class of substances, however, it is unclear how far use of this effect can be made in a toxicologically unproblematic dose. Liao et al. claim in WO 99/47153 and WO 00/03746 the use of rhoGTPase inhibitors and agents which influence the organization of the actin cytoskeleton for increasing eNOS in endothelial cells and for the therapy of various disorders such as, for example, strokes or pulmonary hypertension without, however, indicating a specific way of achieving this. Certain amide derivatives which upregulate the expression of endothelial NO synthase, in particular N-cycloalkyl amides in which the cycloalkyl ring is fused to a benzene ring or a heteroaromatic ring, have been described in WO 02/064146, WO 02/064545, WO 02/064546, WO 02/064565, WO 2004/014369, WO 2004/014372 and WO 2004/014842. Certain triaza- and tetraaza-anthracenedione derivatives which upregulate the expression of endothelial NO synthase have been described in WO 2004/094425. There still exists a need for further compounds which upregulate the expression of endothelial NO synthase and have a favorable property profile and are useful as pharmaceuticals for the treatment of various diseases such as atherosclerosis, coronary artery disease or cardiac insufficiency, for example. Surprisingly it has now been found that the compounds of the formula I are modulators of the transcription of endothelial NO synthase and in particular stimulate, or upregulate, the expression of eNOS, and are useful for the treatment of various diseases such as the mentioned cardiovascular disorders.
Certain heteroarylacrylamides, in which an aryl or heteroaryl group is linked to the heteroaryl substituent on the acrylamide moiety and which are structurally related to formula I, have already been described. For example, in EP 0210782 and in Nishikawa et al., J. Med. Chem. 32 (1989) 583, pyridylacrylamide derivatives are described which comprise a 4-benzhydrylpiperazinylalkyl moiety in the amide group and which exhibit antiallergic activity. In WO 01/62709 and WO 01/70026 phenylenediamine derivatives are described which are antiinfectives and herbicides and which, among others, are N-benzoylphenyl-substituted furylacrylamide and thiazoylacrylamide derivatives carrying a phenyl substituent on the furyl group and thiazolyl group. In Bohm et al., J. Med. Chem. 44 (2001) 3117, it is described that the latter compounds are also inhibitors of farnesyl transferase and potential cancer drugs. In Schlitzer et al., J. Pharmacy Pharmacology 53 (2001) 831, nitrophenylfurylacrylamides and phenylthiazolylacrylamides are described which comprise a carboxy-substituted or methoxycarbonyl-substituted alkyl group in the amide group and which are aldose reductase inhibitors. The compounds described in JP 5-345772, which are inhibitors of acetylcholine esterase useful for the treatment of CNS diseases, include phenylthiazolylacrylamides which comprise a benzylpiperidinyl moiety in the amide group. In EP 0402246 and EP 0489660 N-vinyl-substituted heteroarylacrylamides and other vinyl compounds are described which are fungicides, insecticides and acaricides and which are characterized by an oxy substituent, such as alkoxy, and a methoxycarbonyl substituent on the vinyl group.
An intermediate in the preparation of such compounds is (3-(2-(2-ethylthiazol-4-yl)-thiazol-4-yl)-acryloyl)-methyl-amino-acetic acid methyl ester. 2-(2-Phenylthiazol-4-yl)acrylamide, which is unsubstituted in the amide group, is described in GB 1237194 which relates to compounds having anti-inflammatory activity. In WO 02/040458 (EP 1340749) isoxazole derivatives are described which promote the secretion of insulin and which include isoxazol-4-ylacrylamides in which the isoxazole group carries a cyclic group, such as isoxazol-4-ylacrylamides in which the isoxazole group is substituted by unsubstituted phenyl in the 5-position and optionally by methyl in the 3-position. In WO 03/057215 it is described that such isoxazole derivatives also accelerate the production/secretion of neurotrophic factor. Among the amides described in WO 02/20484, which are characterized by a 4-phenoxypiperidin-1-ylalkyl moiety in the amide group and which are modulators of chemokine and H1 receptor activity useful for the treatment of asthma or rhinitis, are some pyridylacrylamides. In WO 96/16040 and US 2003/0018025, which relate to brain dopamine agonistic and antagonistic imidazolylalkylamine derivatives, certain 1-(2-(4-phenylimidazol-4(5)-yl)acryloyl)-piperazines and -piperidines are described as intermediates which comprise a phenyl or heteroaryl group in the piperazine group and the piperidine group and which can be reduced to the respective imidazolylalkylamine derivatives. In U.S. Pat. No. 5,198,014 and U.S. Pat. No. 5,250,504 herbicidal 3-(4-cyano-1H-pyrazol-5-yl)-acrylic acid derivatives are described which are substituted by an optionally substituted phenyl or pyridin-2-yl group in the 1-position of the pyrazol-5-yl group, which compounds may also be regarded as 3-(4-cyano-2H-pyrazol-3-yl)-acrylic acid derivatives which carry the said phenyl or pyridinyl group in the 2-position of the pyrazol-3-yl group. Some further specific heteroarylacrylamides are known such as the compound (E)-3-[6-(2,6-diethylphenyl)-4-ethyl-2-methylpyridin-3-yl]-1-(piperidin-1-yl)-propenone which is described in WO 2004/043925 which relates to compounds acting as ligands of C5a receptors. A stimulating effect of known heteroarylacrylamides on the transcription or the expression of eNOS and their use in the treatment of diseases which is based on such effect, has not been described.